The long-term goal of this project is to develop a novel oncolytic vaccinia virus (VV) for the treatment of advanced stage solid tumors. The prognosis for patients with advanced stage solid tumors remains poor and bio-therapeutics such as VVs have the potential to improve outcomes. While VVs have shown promising antitumor activity in early Phase clinical studies, few patients have been cured. This lack of efficacy is most likely due to the inability of VVs to kill all tumor cells and/or induce effective antitumoral immune responses. Tumor associated macrophages (TAMs) are key players in promoting tumor growth and creating an immunosuppressive tumor microenvironment. However, recent studies have shown that the inherent phagocytic capacity of TAMs can be harnessed to induce antitumor responses by blocking CD47 on tumor cells and provision of an opsonization signal using a chimeric molecule that consists of the high affinity ectodomain of SIRP? fused to the Fc region of IgG4 (SIRP?-Fc). We now propose to adapt this approach to oncolytic VVs and hypothesize that an oncolytic VV that is genetically modified to express SIRP?-Fc (SIRP?-Fc-VV) will have enhanced antitumor activity in comparison to unmodified VV. Local production of SIRP?-Fc should also be superior to the intermittent direct infusion of the protein, both because the concentration of SIRP?-Fc should be highest at the sites of tumor and because it reduces the risks of unwanted side effects associated with the systemic administration of SIRP?-Fc. Since macrophages are potent antigen presenting cells, we hypothesize further that SIRP?-Fc-VV-induced phagocytosis of tumor cells by macrophages will result in the induction of tumor associated antigen (TAA)-specific T cells. We propose to test our hypotheses in 2 interrelated research aims. Aim 1 generates SIRP?-Fc-VV and SIRP?-VV, and compares their ability to replicate in tumor cells and activate macrophages in vitro. Aim 2 will then evaluate the antitumor activity of SIRP?-Fc-VV and SIRP?-VV in the B16 melanoma model, and assess their ability to induce B16 TAA-specific T-cell responses. If successful, this approach could be readily applied to oncolytic viruses that are currently being developed for a broad range of solid tumors.